Background Huntingtons Disease (HD) is a genetic neurological disorder caused by a trinucleotide CAG repeat expansion in the gene that encodes for the Huntingtin protein. HD leads to progressive movement, psychiatric and cognitive disturbances. In normal rodents physical activity has been shown to enhance hippocampal neurogenesis, neurotrophin levels and learning. Here we aim to determine whether onset and progression of HD may be slowed down by voluntary exercise in a running wheel. Specifically, we use the (N171-82Q) Huntingtons mouse model to investigate the effects of voluntary exercise on motor function, hippocampal neurogenesis, learning, and lifespan. Methods Subjects. Transgenic N171-82Q mice (provided by D.R. Borchelt, Johns Hopkins University) express a human N-terminal truncated huntingtin with 82 polyglutamine repeats driven by a mouse prion protein promoter (2) were mated with B6C3F1 mice. Male and female HD heterozygotes and non- trangenic controls, 5-6 weeks old, were individually housed in standard cages with or without a running wheel (n=17-24 mice per group). During the first ten days of the experiment, mice were injected with bromodeoxyuridine (BrdU, Sigma, St. Louis MO; 50 mg/kg) to label dividing cells. Females were perfused and brains were fixed at 13 weeks of age. Males were kept for further behavior and survival analysis. Spatial Learning. Mice were trained in the Morris water maze after one month of housing under sedentary or running conditions for nine consecutive days with four trials per day. The latency to the platform, length of swim path, and swim speed were recorded semi-automatically by a video tracking system (HVS Image 2020 Plus). On day nine, the platform was removed for a probe trials 4 and 24 hours after the last training session. Novel Object Recognition. Mice were habituated to testing room for 30 minutes for three consecutive days before testing. On day one mice were videotaped and exposed for 15 minutes to either identical blue 50 ml conical caps or identical black paper clamps. On day two mice were videotaped and exposed for 15 minutes to both familiar and novel objects. Interaction with familiar and novel objects will be analyzed using video tracking software (ANY-maze , Wood Dale IL). Health Assessment. Biweekly health assessments were performed to determine HD progression, mouse health, and mouse life expectancy. Tests evaluated mouse weight, glucose levels, and common HD symptoms including hunched back, poor grooming, involuntary shaking (chorea), enlarged abdomen, hind leg clinching, and inactivity. Motor Skills. Mouse motor skills were examined via running distance, rotarod performance, and the activity chamber. Running distances were recorded in kilometers daily through a mini-computer (Sigma Sport, Batavia IL). Rotarod tests were performed weekly for 300 seconds and at 32 rpm. Open field test was performed once for a duration of twenty minutes per mouse (Med Associates Inc, St. Albans VT). Immunohistochemistry. BrdU staining was performed on a 1 in 6 series of free-floating 40-m coronal sections that were pretreated by denaturing the DNA, as described in the literature. Average running distance per week was measured. It was observed that wild-type mice consistently ran more (longer distances) than HD mice. Mouse weight was recorded each week. Only the males were examined for their entire lifespan and demonstrate a significant drop in weight starting at about 17 weeks of age. We analyzed data pertaining to blood glucose levels, performance on the spatial water maze and hippocampal neurogenesis. Our work was published in PLoS Currents Huntington's Disease and we are following up with another mouse model (R6/2 and R6/1 transgenic mice) of the disease.